consequencesininfantsthatwere...

Hindawi Publishing CorporationJournal of PregnancyVolume 2011, Article ID 364381, 6 pagesdoi:10.1155/2011/364381

Review Article

Consequences in Infants That WereIntrauterine Growth Restricted

Erich Cosmi,1 Tiziana Fanelli,1 Silvia Visentin,1 Daniele Trevisanuto,2

and Vincenzo Zanardo2

1 Department of Gynecological Science and Human Reproduction, Maternal Fetal Medicine Unit, School of Medicine,University of Padua, Padua 35128, Italy

2 Department of Pediatrics, School of Medicine, University of Padua, Padua 35128, Italy

Correspondence should be addressed to Erich Cosmi, [email protected]

Received 28 November 2010; Accepted 23 January 2011

Academic Editor: Federico Prefumo

Copyright © 2011 Erich Cosmi et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Intrauterine growth restriction is a condition fetus does not reach its growth potential and associated with perinatal mobility andmortality. Intrauterine growth restriction is caused by placental insufficiency, which determines cardiovascular abnormalities inthe fetus. This condition, moreover, should prompt intensive antenatal surveillance of the fetus as well as follow-up of infants thathad intrauterine growth restriction as short and long-term sequele should be considered.

1. Introduction

Fetuses with impaired intrauterine growth resulting fromplacental insufficiency are at increased risk of adverse short-and long-term outcome [1]. In fact, intrauterine growthrestriction (IUGR) is a major cause of perinatal mortalityand morbidity, and it is associated with several healthproblems throughout life. Current perinatal management ofIUGR fetuses is primarily aimed at deciding the optimal tim-ing of delivery, followed by neonatal intensive interventionto achieve optimal growth rates in order to avoid adverseperinatal complications [2].

IUGR can be regarded as a failure of a fetus that sufferednutritional deprivation to reach its genetic growth potential[3]. This is principally a vascular disorder, which consistsof impaired fetal growth and in fetal multivessel cardio-vascular manifestations [1]. The fetal circulatory responseto placental insufficiency includes redistribution of thearterial circulation with preferential distribution of cardiacoutput towards the left ventricle, which mainly maintains anadequate oxygen supply to both the brain and the hearth.With further fetal deterioration, cardiac dysfunction resultsin abnormal venous flow velocity profiles, including reverseflow in the ductus venosus during atrial contraction andatrial pulsations in the umbilical vein.

Moreover, fetal cardiac function differs in IUGR com-pared to AGA fetuses as placental insufficiency affects fetalhearth. In fact, IUGR fetuses show an altered cardiac func-tion in both systolic and diastolic phase, which determinean earlier and more pronounced right than left and diastolicthan systolic fetal cardiac function deterioration [4].

Fetuses are classified as IUGR if estimated fetal weight(EFW) is below the 10th percentile and umbilical arterypulsatility index (PI) > 2 SD.

2. Short-Term Outcome

Intrauterine growth restriction is of huge importancein obstetric practice. A modern classification system ofstillbirth, ReCoDe, has shown that IUGR is the mostcommon factor identified in stillborn babies. In addi-tion, it has serious consequences for babies who survive.IUGR is associated with increased risk of premature birth;increased morbidity among premature neonates, includingnecrotizing enterocolitis; low Apgar score; hypoxic braininjury and its long-term sequelae; the need for respiratorysupport and chronic lung disease; retinopathy of prema-turity; prolonged neonatal intensive care unit (NICU),and mortality [3]. Furthermore, a number of causes ofIUGR are associated with an increased risk of IUGR and

2 Journal of Pregnancy

intrauterine death (IUD) in mother’s subsequent pregnancy[5].

The perinatologist plays a fundamental role in diag-nosing the presence and cause of IUGR in pregnancy toavoid major consequences, through ultrasound assessmentof estimated fetal weight and Doppler examination of fetalcirculation. In particular, it appears to be a link between thelength of intrauterine deficit and perinatal outcome.

3. The Barker Hypothesis and FetalProgramming of Adult Disease

Low birth weight, caused either by preterm birth and/orintrauterine growth restriction, was recently known to beassociated with increased rates of cardiovascular disease andnoninsulin-dependent diabetes in adult life [6–10].

The “developmental origins of adult disease” hypothesis,often called “the Barker hypothesis” proposes that thesediseases originate through adaptations of the fetus when itis undernourished. These adaptations may be cardiovascular,metabolic, or endocrine, and they may permanently changethe structure and function of the body, increasing coronaryheart disease risk factors, such as hypertension, type 2 dia-betes mellitus, insulin resistance, and hyperlipidaemia [11–14]. This hypothesis originally involved from observation byBarker and colleagues that the regions in England with thehighest rates of infant mortality in the early 20th centuryalso had the highest rates of mortality from coronary heartdisease decades later. As the most commonly registered causeof infant death at the start of 20th century was low birthweight, these observations led to the hypothesis that low-birth-weight babies who survived infancy and childhoodmight be at increased risk of coronary heart disease in laterlife [15].

As Barker and his colleagues reported in several epi-demiological and anthropological studies, in fetal life, tissuesand organs go through the so-called “critical” periods ofdevelopment. These may coincide with periods of rapidcell division. Although the fetal growth is influenced by itsgenes, several studies suggest that it is usually limited byintrauterine environment, in particular the nutrients andoxygen received from the mother. Influence linked to fetaland placental growth have an important effect on the risk ofcoronary heart disease and stroke. Thus, this theory focusingon intrauterine life, offers a new point of departure forresearch in cardiovascular disease. According to the thriftyphenotype hypothesis, deficient fetal supply may be followedby a programming, which includes circulatory adjustmentand insulin resistance in liver and muscular tissue in orderto spare the brain [6–10, 16].

In addition, postnatal overnutrition following intrauter-ine growth restriction may be pathogenetic for the devel-opment of obesity and type 2 diabetes whereas the elevatedcardiovascular mortality rate may be associated with rapidpostnatal catch-up growth in early infancy [17]. Manyreports of relationship between birth size and disadvan-tageous glucose and insulin metabolism have widely beenreviewed. In particular, fetal growth retardation has beenassociated with increased insulin resistance, higher fasting

insulin concentrations, and increased incidence of type 2diabetes. Neonatal abdominal circumference has been shownto predict plasma cholesterol and fibrinogen levels in adultsin later life, which are both risk factors for cardiovasculardisease.

Association between IUGR and raised blood pressure inchildhood and adult life has been extensively demonstratedaround the world. In 1996, a review based on 34 studiesinvolving more than 66.000 persons of all ages identified anegative relationship between birth weight and systolic bloodpressure in childhood and adulthood. This relationshipwas independent of body size at time of blood pressuremeasurement, and its magnitude tended to increase with age[18, 19].

A similar review in 2001 based on 27 independent obser-vational studies also evidenced a mean difference in systolicblood pressure of −1.7 mmHg per kilogram increment inbirth weight. The review also documented a consistentlynegative association between birth weight and diastolic bloodpressure. Besides low birth weight, 3 other early factors thatare considered to be important risk factors for developinghigh blood pressure in adult life have been identified inindividuals with IUGR. First, accelerated postnatal growthin weight and length is suggested to increase the risk fordeveloping hypertension and type 2 diabetes in later life.Second, it was postulated that altered angiotensin activitywas an important factor underlying the “fetal origins of adultdiseases” hypothesis. Also, hypoxia increased sympatheticnerve activity and catecholamine production and prolifer-ation of juxtaglomerular cells (and thus renin-producingcells) are suggested as factors in the pathogenesis [20, 21].A followup study recently published by Cosmi et al. demon-strates that systolic blood pressure measurements in 2-year-old children born intrauterine restricted are significantlyhigher compared to appropriate for gestational age childrenat the same age [22].

From a historical viewpoint, it is clear that the Barkerhypothesis received significant support because of its publichealth implication. However, it must be considered thatmany confounders are known to influence blood pressure inadult life apart from birth weight. In addition, a larger geneticheterogeneity of individuals enrolled may explain its results.However, as stated by Gluckman and Hanson “it is no longerpossible to ignore the developmental phase of life” [23] andfollowup studies in early childhood will assist the medicalcommunity and public health to designing interventions inorder to ensure the best possible fetal development [19].

4. Endothelial Dysfunction

The endothelium controls vascular tone, coagulation, andinflammatory responses. Endothelial dysfunction is an earlyevent of atherosclerosis, preceding structural changes inthe vascular wall. Atherosclerosis is thought to begin inchildhood and to develop silently before clinical events suchas myocardial infarction or stroke occur [24].

As with major cardiovascular risk factors, impairedgrowth in utero is associated with functional (endothe-lial dysfunction) and structural (increased wall thickness)

Journal of Pregnancy 3

changes to the arterial vascular consistent with earlyatherosclerosis. Impaired fetal growth in infants is associatedwith increased sympathetic tone and lipid concentration,and reduced concentration of insulin-like growth factor-1,all of which might contribute to arterial wall thickening.However, these findings are difficult to interpret becauseof potential confounding by, or interaction with, postnatalinfluences, so this hypothesis needs further clarification.Teeninga et al. demonstrated atheromatous changes inthe aorta of children. Atheromatous changes have beendocumented histopathologically by early childhood, andit has been assessed that the first atherosclerotic lesionsactually begin to develop in the abdominal aorta [25].Nowadays, many studies demonstrated atherosclerotic wallthickening in the arteries of children with cardiovascularrisk factors using ultrasound imaging assessing noninvasivelyearly vascular changes.

In 2005, Skilton and coworkers added new interestinginformation to Barker’s hypothesis. They compared intima-media thickness (aIMT) of the aortic wall in newborninfants with low birth weight with normal controls. InIUGR newborns aIMT was significantly greater than in thecontrols. On the basis of these finding, the ultrasound-basedmeasurement of abdominal aortic intima-media thicknessin children was described as a feasible, accurate, andsensitive marker of atherosclerosis risk, and, as there wasno confounding from childhood and adult exposures, theyprovided clear indications for a fetal contribution to later car-diovascular disease [26]. Also, Koklu et al. in 2007, evaluatedthe potential use of aIMT in the study of high-risk neonates,concluding that aIMT measurement in IUGR newborns canhelp in the early identification of asymptomatic vasculardysfunction [27–29]. Recently, Cosmi et al. studied aIMTin fetuses for the first time and then in the same infantsafter a mean followup of 18 months. This study showedthat aIMT measurements in IUGR fetuses were inverselyrelated to estimated fetal weight, showing that low birthweight and Doppler abnormalities may be correlated toan altered vascular structure causing possible endothelialdamage, consistent with the finding that atherosclerosisbegins to develop first in the intima of the aorta. Thesedifferences were present also at the time of followup[30].

Similarly, carotid intima-media thickness has beenshown to be greater in children with low-birth weight. In arecent study, Crispi et al. confirms the presence of increasedcarotid wall thickness in children with IUGR and thatthese changes persist into childhood. The increased arterialwall thickness could be the result of vascular remodelinglinked to metabolic programming in intrauterine restrictedlife [31]. They also highlighted that children with IUGRshow changes in cardiac morphology, subclinical cardiaclongitudinal dysfunction, and hypertension, all of whichincrease linearly with the severity of growth restriction andare independent of gestational age at delivery, lipid profile,or body mass index.

The importance of early identification and interventionin pediatric risk factors for cardiovascular disease is nowwell recognized, and this could open new opportunities

for monitoring and intervention in newborns and childrenaffected with intrauterine growth restriction.

5. Fetal Programming and Renal Consequences

According to the fetal programming, the kidneys too appearto be extremely susceptible to intrauterine growth restrictionand are often found small in proportion to body weight[32]. Several studies in animals and humans have describeda reduced number of nephrons after IUGR. This results inan inborn decreased glomerular filtration surface area whilerenal blood flow per glomerulus is increased in attemptto maintain a normal overall glomerular filtration rate.According to the hyperfiltration hypothesis explained byBrenner and coworkers [33–35] this leads to glomerularhypertension and hypertrophy, which causes systemic hyper-tension and higher sodium reabsorption and glomerulardamage resulting in albuminuria and glomeruloclerosis.Also, premature birth implies a shorter period of activenephrogenesis, as describes by Rodrıguez et al., involvingin impaired renal development [36]. Therefore, IUGR canlead to impairment of renal function. A kidney with areduced nephron number has less renal reserve to adaptto dietary excesses or to compensate for renal injury. Thepathway leading from small kidney to hypertension mayinclude the rennin-angiotensin system, which is altered in theearly phase of primary hypertension. An increased activityof the rennin-angiotensin system could be a compensatorymechanism in a decreased number of nephrons in orderto maintain normal filtration [37]. These mechanisms arewell described in experimental study including IUGR malerats, whose presented higher blood pressure and fewerglomeruli at 22 weeks of age [38]. In the last five years,more clinical data are available regarding maturation ofrenal function in IUGR infants. Keijzer-Veen and colleaguesin 2005, identified a positive association of birth weightand glomerular filtration rate (GFR). The investigatorsalso detected a negative association of birth weight andserum creatinine, suggesting that IUGR individuals are atgreater risk to develop hypertension and progressive renalfailure [39]. This work made a significant contribution tounderstanding mechanism associated with the progressionof cardiovascular disease and intrauterine retardation. Incontrast Rakow et al. found that glomerular filtration rateand urinary protein patterns were similar between IUGR12-year-old children and controls, but kidney volume wassmaller in the first group [40]. A meta-analysis published byTeeninga et al. in 2008, consisted of 201 patients (25 SGA, 176AGA), showed that low birth weight has a strong influence onglomerular filtration rate and proteinuria, associated with ahigher chance of developing several complications, includinghypertension [41]. A recent followup study demonstratedthat 5-year- old children born IUGR showed higher bloodpressure, increased albuminuria, lower GRF, and differenturinary sodium excretion rate than controls. These obser-vations support the contention that extrinsic renal injury isnot a prerequisite for the initiation and perpetuation of renalinjury and that certain circumstances, prenatally derived,intrinsic deficiencies in functioning renal mass may be


sufficient to contribute to renal functional decline occurringwith advancing age.

6. Infant Neurodevelopment

Intrauterine growth restriction plays a significant role inshort- and is long-term outcome and reflected in highincidence of brain dysfunction and neurodevelopmentalimpairment, as well as in somatic growth failure. Theseclinical consequences could not be apparent until later inchildhood development and could involve poor academicperformance, memory, visuomotor, and language difficul-ties, and executive function problems. Several longitudinalstudies have addressed the question of correlation betweencognitive development and somatic growth in IUGR, usinga different questionnaire dealing with aspects of reading,writing, spelling, and mathematics. An increased risk ofcognitive impairment has been demonstrated in childrenwith small head circumference [42]. Shenkin et al. foundthat birth weight is significantly related to IQ at age 11 [43].In other studies, IUGR children have lower nonverbal andverbal IQ than controls [44]. According to data from theNational Collaborative Perinatal Project (1959–1976) the IQscores of 2719 IUGR children tested at age 7 were 6 pointslower than AGA children. Visuomotor development wasalso lower in IUGR group. Besides neurosensory handicaps,also behavioral sequelae are of serious concern. Behavioralproblems, which might manifest only at school age, can havea great impact on school performance and social competenceand have a negative influence on quality of life [45].Learning difficulties and behavioral problems are reportedmore often in IUGR preterm infants compared to AGA[46].

Management of these infants is controversial. They havean increased perinatal mortality and morbidity includingbehavioral problems, minor developmental delay, poorneurosensory development, and spastic cerebral palsy. Def-inition of these important long-term relationships invitesresearch of pathological mechanism. Recent advanced mag-netic resonance imaging studies have shown that IUGR isassociated with structural differences that can be identifiedvery early in life, such as reduction in cerebral corticalgrey matter, hippocampal volume, and sulcation index.These macrostructural alterations have been associated withmicrostructural and metabolic changes [47]. As explainedby Baschat et al. [48], the IUGR fetus “enables” sparingof the head while growing in a low-nutrient intrauterineenvironment and has neuroadaptative modification aimedat preserving brain oxygen supply in presence of chronichypoxia. This process is identified clinically by a reducedDoppler pulsatility index (PI) in the middle cerebral artery(MCA) [49]. When multiple parameters are considered,such as gestational age and birth weigh, umbilical arteryreversed end diastolic velocity (UA-REDV) is identified asan important contributor to neurodevelopment. No similareffect could be demonstrated for abnormal venous Dopplerfindings. Brain sparing and cerebral arteries Doppler resultsare objects of study as predictors of adverse neurologicaloutcome, but these relationships are not well assessed

[45, 50]. These findings have important implications forthe prognosis and the management of intrauterine growthrestricted fetuses and children, who should be closelyfollowed up to identified individuals at risk [42].

7. Conclusions

The importance of IUGR in understanding adverse preg-nancy outcome is relevant not only for clinicians, but also forpublic health service. During the last decade, knowledge ofthe short-term and long-term consequences of impaired fetalgrowth has increased at a very rapid rate and has involvedlots of clinical aspects. At present, it is most importantnot only to develop efficient methods of preventing anddiagnosing IUGR, recognizing at-risk fetuses, and screeningfetal growth restriction among low-risk pregnancies, but towork out followup and adequate treatment programs for thecontrol of the disorders which may follow this conditions.Programming the right time to deliver is the best method toavoid adverse perinatal outcome; indeed, proper postnatalfeeding and infant growth may be essential for long-termoutcome.

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